Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

GABA(B) receptors are believed to play a role in rhythmic activity in the mammalian brain. The aim of our study was to examine the presynaptic and postsynaptic locations of these receptors in the medial septal diagonal band area (MS/DB), an area known to pace the hippocampus theta rhythm. Whole-cell patch recordings were made from parasagittal MS/DB slices obtained from the 16-25 day rat. Neurons were classified into GABAergic and cholinergic subtypes according to previous electrophysiological criteria. Bath application of the GABA(B) receptor agonist baclofen in the presence of tetrodotoxin, and brief tetanic fiber stimulation in the presence of ionotropic receptor antagonists, provided evidence for the presence of postsynaptic GABA(B) receptor transmission to GABAergic but not cholinergic neurons. Bath application of baclofen, at concentrations too low to elicit postsynaptic activity in MS/DB neurons, significantly reduced the amplitudes of stimulus-evoked ionotropic receptor inhibitory postsynaptic potentials (IPSPs) and excitatory postsynaptic potentials (EPSPs) and the paired pulse depression of these evoked potentials. Baclofen also significantly reduced the frequencies but not the amplitudes of miniature inhibitory postsynaptic currents (IPSCs) and excitatory postsynaptic currents (EPSCs), indicating the presence of presynaptic GABA(B) receptors on GABAergic and glutamatergic terminals in the MS/DB. Baclofen, also at a concentration too low to elicit postsynaptic activity, reduced the frequencies and amplitudes of spontaneous IPSCs and EPSCs recorded in the presence of 200-400 nM kainate. Rhythmic compound IPSCs at theta frequencies were recorded under these conditions in some neurons, and these rhythmic compound IPSCs were disrupted by the activation but not by the inhibition of GABA(B) receptors. These results suggest that GABA(B) receptors modulate rather than generate rhythmic activity in the MS/DB, and that this modulatory effect occurs via receptors located on presynaptic terminals.
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PMID:GABAB receptors in the medial septum/diagonal band slice from 16-25 day rat. 1583 39

Enaminones are a novel group of compounds that have been shown to possess anticonvulsant activity in in vivo animal models of seizures. The cellular mechanism by which these compounds produce their anticonvulsant effects is not yet known. This study examined the effects of enaminones on excitatory synaptic transmission. We studied the effects of 3-(4'-chlorophenyl)aminocyclohex-2-enone (E118), methyl 4-(4'-bromophenyl)aminocyclohex-3-en-6-methyl-2-oxo-1-oate (E139) and ethyl 4-(4'-hydroxyphenyl)aminocyclohex-3-en-6-methyl-2-oxo-1-oate (E169) on isolated evoked, glutamate-mediated excitatory synaptic responses by recording whole-cell currents and potentials in cells of the nucleus accumbens (NAc) contained in forebrain slices. The anticonvulsant enaminones (E118 and E139), but not E169, depressed NMDA and non-NMDA receptor-mediated synaptic responses. The inhibition of the non-NMDA response was concentration-dependent (1.0-100 microM) with a maximal depression of approximately -30%. E118 and E139 had similar potencies (EC(50)=3.0 and 3.5 microM, respectively) in depressing this response but E139 was more efficacious (E(max)=-31.3+/-3.8%) than E118 (E(max)=-22.6+/-1.6%). The excitatory postsynaptic current (EPSC) depression caused by 10 microM E139 (-27.7+/-3.8%) was blocked by 1 microM CGP55845 (6.3+/-8.1%), a potent GABA(B) receptor antagonist. Pretreatment of slices with gamma-vinylGABA and 1-(2-(((diphenylmethylene)imino)oxy)ethyl)-1,2,5,6-tetrahydro-3-pyridine-carboxylic acid (NO-711), an irreversible GABA transaminase (GABA-T) inhibitor and a GABA reuptake blocker, respectively, like the anticonvulsant enaminones, also caused a depression of the evoked EPSC (-38.1+/-14.1 and -24.1+/-8.9%, respectively). In the presence of these compounds, E139 did not cause a further depression of the EPSC. Our data suggest that anticonvulsant enaminones cause EPSC depression by enhancing extracellular GABA levels possibly through the inhibition of either GABA reuptake or GABA-T enzyme, or both.
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PMID:Anticonvulsant enaminones depress excitatory synaptic transmission in the rat brain by enhancing extracellular GABA levels. 1591 38

GABA(B) receptors are a member of the G protein-coupled family of receptors which are generally considered to be excellent drug targets. Cloning of the GABA(B) receptor demonstrated that, unlike other G protein-coupled receptors, it is an obligate heterodimer. Drugs acting at GABA(B) receptors have the potential to treat a wide variety of diseases. Activation of the receptors may have utility in the treatment of pain, drug-dependence, and anxiety, whereas blockade of receptors may have benefit in cognitive disorders and depression. To date, development of drugs has been hampered by the lack of receptor subtypes and the inability to separate therapeutic benefit from side effects such as sedation. Recently, novel compounds that act via an allosteric mechanism have been identified and are providing hope that future drugs may be developed that target this receptor.
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PMID:Is the GABA B heterodimer a good drug target? 1601 90

GABA(B) receptor (GABA(B)R)-mediated presynaptic inhibition regulates neurotransmitter release from synaptic terminals. In the neonatal hippocampus, GABA(B)R activation reduces GABA release and terminates spontaneous network discharges called giant depolarizing potentials (GDPs). Blocking GABA(B)Rs transforms GDPs into longer epileptiform discharges. Thus, GABA(B)R-mediated presynaptic inhibition of GABA release (GABA auto-inhibition) controls both spontaneous network activity and excitability in the developing hippocampus. Here we show that extensive release of endogenous GABA during epileptiform activity impairs GABA auto-inhibition, but not GABA(B)R-mediated inhibition of glutamate release, leading to hyperexcitability of the neonatal hippocampal network. Paired-pulse depression of GABA release (PPD) and heterosynaptic depression of glutamate release were used to monitor the efficacy of presynaptic GABA(B)R-mediated inhibition in slices. PPD, but not heterosynaptic depression, was dramatically reduced after potassium (K+)-induced ictal-like discharges (ILDs), suggesting a selective impairment of GABA(B)R-dependent presynaptic inhibition of GABAergic terminals. Impairing GABA auto-inhibition induced a 44% increase in GDP width and the appearance of pathological network discharges. Preventing GABA-induced activation of GABA(B)Rs during ILDs avoided PPD loss and most modifications of the network activity. In contrast, a partial block of GABA(B)Rs induced network discharges strikingly similar to those observed after K+-driven ILDs. Finally, neither loss of GABA auto-inhibition nor network hyperexcitability could be observed following synchronous release of endogenous GABA in physiological conditions (during GDPs at 1 Hz). Thus, epileptiform activity was instrumental to impair GABA(B)R-dependent presynaptic inhibition of GABAergic terminals. In conclusion, our results indicate that endogenous GABA released during epileptiform activity can reduce GABA auto-inhibition and trigger pathological network discharges in the newborn rat hippocampus. Such functional impairment may play a role in acute post-seizure plasticity.
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PMID:Epileptiform activity triggers long-term plasticity of GABA(B) receptor signalling in the developing rat hippocampus. 1609 37

Clinical and experimental evidence indicates that the amygdala is involved in limbic seizures observed in patients with temporal lobe epilepsy. Here, we used simultaneous field and intracellular recordings from horizontal brain slices obtained from pilocarpine-treated rats and age-matched nonepileptic controls (NECs) to shed light on the electrophysiological changes that occur within the lateral nucleus (LA) of the amygdala. No significant differences in LA neuronal intrinsic properties were observed between pilocarpine-treated and NEC tissue. However, spontaneous field activity could be recorded in the LA of 21% of pilocarpine-treated slices but never from NECs. At the intracellular level, this network activity was characterized by robust neuronal firing and was abolished by glutamatergic antagonists. In addition, we could identify in all pilocarpine-treated LA neurons: 1) large amplitude depolarizing postsynaptic potentials (PSPs) and 2) a lower incidence of spontaneous hyperpolarizing PSPs as compared with NECs. Single-shock stimulation of LA networks in the presence of glutamatergic antagonists revealed a biphasic inhibitory PSP (IPSP) in both NECs and pilocarpine-treated tissue. The reversal potential of the early GABA(A) receptor-mediated component, but not of the late GABA(B) receptor-mediated component, was significantly more depolarized in pilocarpine-treated slices. Furthermore, the peak conductance of both fast and late IPSP components had significantly lower values in pilocarpine-treated LA cells. Finally, paired-pulse stimulation protocols in the presence of glutamatergic antagonists revealed a less pronounced depression of the second IPSP in pilocarpine-treated slices compared with NECs. Altogether, these findings suggest that alterations in both pre- and postsynaptic inhibitory mechanisms contribute to synaptic hyperexcitability of LA networks in epileptic rats.
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PMID:Altered inhibition in lateral amygdala networks in a rat model of temporal lobe epilepsy. 1638 2

We recently reported that the activation of cholecystokinin-2 receptors depress evoked excitatory postsynaptic currents (EPSCs) in nucleus accumbens (NAc) indirectly through gamma-aminobutyric acid (GABA) acting on gamma-aminobutyric acid-B (GABA(B)) receptors. Here, we determined the second messenger system that couples cholecystokinin-2 receptors to the observed synaptic depression. Using in vitro forebrain slices of rats and whole-cell patch recording, we tested the hypothesis that cholecystokinin-2 receptors are coupled to cAMP and protein kinase A signaling pathway. Cholecystokinin-8S induced inward currents and depressed evoked EPSCs. Forskolin, an activator of adenylyl cyclase and rolipram that is an inhibitor of phosphodiesterase type IV, independently increased EPSC amplitude and blocked the inward current and synaptic depression induced by cholecystokinin-8S. Furthermore, the membrane-permeable cAMP analog, 8-bromo-cAMP, blocked the cholecystokinin-8S effects. H89, a protein kinase A inhibitor, also blocked cholecystokinin-8S effects. However, depression of the evoked EPSC by baclofen, a GABA(B) receptor agonist, was not blocked by H89 or forskolin. These findings indicate that cholecystokinin-2, but not GABA(B), receptors are coupled to the adenylyl cyclase-cAMP-protein kinase A signaling pathway in the NAc to induce inward currents and cause synaptic depression.
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PMID:Cholecystokinin-2 receptors couple to cAMP-protein kinase A to depress excitatory synaptic currents in rat nucleus accumbens in vitro. 1690 Sep 46

Cholecystokinin-positive (CCK+) basket cells are a major source of perisomatic GABAergic inputs to CA1 pyramidal cells. These interneurons express high levels of presynaptic cannabinoid type 1 (CB1) receptors that mediate short-term depression of GABA release following depolarization of postsynaptic cells. However, it is not known whether GABA release from CA1 CCK+ basket cells is under tonic endocannabinoid inhibition. In paired patch-clamp recordings, action potentials in presynaptic CCK+ basket cells evoked large IPSCs with fast kinetics in pyramidal cells. The proportion of action potentials that failed to evoke GABA release varied markedly between pairs, from highly reliable to virtually silent connections. Application of the CB1 receptor antagonist AM251 (10 microm) decreased the proportion of failures, revealing a persistent suppression of synaptic transmission by CB1 receptors. However, AM251 had no significant effect on the failure rate when the calcium chelator BAPTA (10 mm) was introduced into the postsynaptic cell, indicating that the tonic inhibition of GABA release by CB1 receptors is homosynaptically controlled by the postsynaptic cell, and that it is not due to constitutive CB1 receptor activity. Application of muscarinic or metabotropic glutamate receptor agonists inhibited synaptic transmission exclusively through the release of endocannabinoids from postsynaptic cells in a manner that could not be blocked by postsynaptic BAPTA, and had no direct effect on transmission. In contrast, GABA(B) receptor activation directly blocked GABA release, but there was no evidence for tonic inhibition of GABA release by GABA(B) receptors. Neither serotonergic nor mu-opioid agonists had significant influence on GABA release from CCK+ axon terminals. These results reveal that GABA release from CA1 CCK+ basket cells is under homosynaptic tonic inhibition by endocannabinoids, and it is subject to both direct and indirect modulation by various G-protein-dependent neuromodulators.
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PMID:Postsynaptic origin of CB1-dependent tonic inhibition of GABA release at cholecystokinin-positive basket cell to pyramidal cell synapses in the CA1 region of the rat hippocampus. 1708 27

We recently reported that anticonvulsant anilino enaminones depress excitatory postsynaptic currents (EPSCs) in the nucleus accumbens (NAc) indirectly via gamma-aminobutyric acid (GABA) acting on GABA(B) receptors [S.B. Kombian et al. (2005)Br. J. Pharmacol., 145, 945-953]. Norepinephrine (NE) and dopamine (DA), both known to be involved in seizure disorders, also depress EPSCs in this nucleus. The current study explored a possible interaction between enaminones and adrenergic and/or dopaminergic mechanisms that may contribute to their synaptic depression and anticonvulsant effect. Using whole-cell recording in rat forebrain slices containing the NAc, we show that NE-induced, but not DA-induced, EPSC depression occludes E139-induced EPSC depressant effect. UK14,304, a selective alpha(2) receptor agonist, mimicked the synaptic effect of NE and also occluded E139 effects. Phentolamine, a non-selective alpha-adrenergic antagonist that blocked NE-induced EPSC depression, also blocked the E139-induced EPSC depression. Furthermore, yohimbine, an alpha(2)-adrenoceptor antagonist, also blocked the E139-induced EPSC depression, while prazosin, a selective alpha(1)-adrenergic antagonist, and propranolol, a non-selective beta-adrenoceptor antagonist, did not block the E139 effect. Similar to the E139-induced EPSC depression, the NE-induced EPSC depression was also blocked by the GABA(B) receptor antagonist, CGP55845. By contrast, however, neither SCH23390 nor sulpiride, D1-like and D2-like DA receptor antagonists, respectively, blocked the E139-induced synaptic depression. These results suggest that NE and E139, but not DA, employ a similar mechanism to depress EPSCs in the NAc, and support the hypothesis that E139, like NE, may act on alpha(2)-adrenoceptors to cause the release of GABA, which then mediates synaptic depression via GABA(B) receptors.
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PMID:Enaminones and norepinephrine employ convergent mechanisms to depress excitatory synaptic transmission in the rat nucleus accumbens in vitro. 1715 4

Neocortical networks play a major role in the genesis of generalized spike-and-wave (SW) discharges associated with absence seizures in humans and in animal models, including genetically predisposed WAG/Rij rats. Here, we tested the hypothesis that alterations in GABA(B) receptors contribute to neocortical hyperexcitability in these animals. By using Real-Time PCR we found that mRNA levels for most GABA(B(1)) subunits are diminished in epileptic WAG/Rij neocortex as compared with age-matched non-epileptic controls (NEC), whereas GABA(B(2)) mRNA is unchanged. Next, we investigated the cellular distribution of GABA(B(1)) and GABA(B(2)) subunits by confocal microscopy and discovered that GABA(B(1)) subunits fail to localize in the distal dendrites of WAG/Rij neocortical pyramidal cells. Intracellular recordings from neocortical cells in an in vitro slice preparation demonstrated reduced paired-pulse depression of pharmacologically isolated excitatory and inhibitory responses in epileptic WAG/Rij rats as compared with NECs; moreover, paired-pulse depression in NEC slices was diminished by a GABA(B) receptor antagonist to a greater extent than in WAG/Rij rats further suggesting GABA(B) receptor dysfunction. In conclusion, our data identify changes in GABA(B) receptor subunit expression and distribution along with decreased paired-pulse depression in epileptic WAG/Rij rat neocortex. We propose that these alterations may contribute to neocortical hyperexcitability and thus to SW generation in absence epilepsy.
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PMID:Reduced GABAB receptor subunit expression and paired-pulse depression in a genetic model of absence seizures. 1720 29

In the serum and cerebrospinal fluid of a patient with recurrent acute episodes of respiratory crises, autonomic symptoms and total insomnia (agrypnia), we identified a novel anti-neural complement fixing antibody directed against GABA(B) receptor (GABA(B)R). Patient purified IgG recognized a band of approximately 110 kDa on protein extracts of mouse cerebellum, cortex and brainstem and immunolabelled cultured Chinese hamster ovary (CHO) cells, transfected with human GABA(B)R1 and rat GABA(B)R2 receptors. Western blot analysis of transfected CHO homogenates showed the same band using both patient purified IgG and anti-GABA(B)R1 antibody. In order to verify the pathogenic role of these purified antibodies, we injected patient IgG intrathecally into cisterna magna of C57BL/6 mice pre-implanted with EEG electrodes and we observed severe ataxia followed by breathing depression and total suppression of slow wave sleep, as evidenced by EEG recording, in a dose-dependent manner. Immunohistochemistry on brain sections of mice injected with patient IgG showed the simultaneous presence of bound human IgG and C5b-9 deposits on Purkinje cells and cerebellar granular layer. After incubation with anti-GABA(B)R antibody, a marked reduction of receptor immunostaining was found with relative sparing of neuronal architecture. In conclusion we recognized an anti-neuronal autoantibody directed against GABA(B)R that is associated with autoimmune agrypnia and we showed that our patient purified IgG was able to induce in mice experimental autoimmune agrypnia characterized by a complex neurological syndrome affecting several CNS functions.
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PMID:A human anti-neuronal autoantibody against GABA B receptor induces experimental autoimmune agrypnia. 1733 94


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